Contents

Overview

The shapes and actions of receptors are newly investigated by the X-ray crystallography and computer modelling. This increases the current understanding of drug action at binding sites on the receptors.

Binding and activation

Ligand binding to a receptor is an equilibrium process: Ligands bind to an empty receptor and they dissociate from it (according to the law of mass action):

:

(the brackets stand for concentrations)

A measure of how well a certain molecule fits into a given receptor is the binding affinity which is measured as the dissociation constant Kd (good fit means high affinity and a low Kd). The activation of the second messenger cascade and the final biological response is achieved only when at a certain time point a significant number of receptors are activated by bound ligands.

If the receptor exists in two states (see this picture), then the ligand binding must account for these two receptor states. For a more detailed discussion of two-state binding, which is thought to occur as an activation mechanism in many receptors see this link.

Constitutive activity

Receptors which are active in the absence of a ligand. The constitutive activity of these receptors may be reversed by inverse agonist binding. Mutations in receptors that result in increased constitutive receptor signaling underlie some heritable diseases, such as precocious puberty (luteinizing hormone receptor mutations) and hyperthyroidism (thyroid-stimulating hormone receptor mutations). Psychostimulants act as inverse agonists at dopamine receptors.

For the use of statistical mechanics in a quantitative study of the
ligand-receptor binding affinity, see the comprehensive article[1].

Transcription factors

Various

Role in Genetic Disorders

Many genetic disorders involve hereditary defects in receptor genes. Often, it is hard to determine whether the receptor is nonfunctional or the hormone is produced at decreased level; this gives rise to the "pseudo-hypo-" group of endocrine disorders, where there appears to be a decreased hormonal level while in fact it is the receptor that is not responding sufficiently to the hormone.

Ligand-bound desensitation of receptors was first characterized by Katz and Thesleff in the nicotine acetylcholine receptor[4][5] Prolonged or repeat exposure to a stimulus often results in decreased responsiveness of that receptor for a stimulus. Receptor desensitization results in altered affinity for the ligand.[4] Receptor desensitization can modeled by a two-state model that also predicts that antagonists combined with agonists can prevent receptor desensitization [6] See this link [1] for detailed molecular description